The regulation of the transcription factor NRF2 opens a therapeutic window for a host of chronic degenerative diseases, such as diabetes and its complications, cancer, obesity, neurodegenerative diseases, kidney diseases, immunological diseases, and so on. The ability to regulate cytoprotective functions such as antioxidant defenses or pro-apoptotic or anti-apoptotic functions is of utmost importance. Currently, there are therapeutic agents to activate or inhibit NRF2; research should focus on understanding how NRF2 makes "the decision" to perform one function or another.